Throughout the world Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen. In areas with poor sanitary conditions C. trachomatis causes trachoma, the most common cause of preventable blindness in the world. A majority of the genital C. trachomatis infections in women are asymptomatic. In addition, in symptomatic cases, unless therapy is implemented in a timely manner, long-term sequelae, including pelvic inflammatory disease, chronic abdominal pain, ectopic pregnancy and infertility, may develop. Thus, the only practical approach to prevent these diseases is vaccinating the population at risk. In this proposal we want to test the hypothesis that a vaccine formulated with the C. trachomatis major outer membrane protein (MOMP) can induce protection in female mice against a genital challenge. To achieve this goal we want to utilize a recombinant MOMP preparation of the mouse pneumonitis (MoPn) serovar expressed in Escherichia coli. We will first optimize the vaccination protocol in BALB/c mice for the route and adjuvant formulation so as to induce strong systemic and mucosal immune responses. Mice will be challenged in the genital tract at four weeks after the last immunization. Parameters of protection will include: histopathological changes in the genital tract, percentage of mice with positive vaginal cultures and severity and length of vaginal shedding. The optimized vaccine will then be tested for its ability to protect C3H/HeN and C57BL/6 mice. Protection against long-term sequelae will subsequently be evaluated by determining fertility rates and the number of embryos per pregnant animal. The vaccine will also be tested for its efficacy for inducing long-term protection. Specifically, vaccinated animals will be challenged in the genital tract at 60, 120 and 180 days after the last immunization. Finally, cross-protection will be established by vaccinating mice with recombinant MOMP preparations from MoPn and selected human serovars and determining their efficacy to protect against a challenge with the other human serovars. In conclusion, our goal is to establish a vaccination protocol utilizing a recombinant MOMP preparation to protect against a genital challenge with C. trachomatis. An efficacious vaccine against C. trachomatis will have a tremendous sanitary and economic impact throughout the world.